Prenatal caffeine exposure impairs neurodevelopment via glucocorticoid-driven epigenetic cascade suppressing astrocytic ABCG1 and cholesterol transport

Gaole Dai, Mingcui Luo,Shiyun Dai,Xinli Zhou,Sen Zhu,Mengxi Lu,Xiaoyi Han,Fang Yang,Ying Yu, Hui Wang, Dan Xu

Metabolism 2026

https://doi.org/10.1016/j.metabol.2025.156454

Abstract

Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological studies have consistently linked PCE to cognitive impairments and emotional deficits in offspring, the underlying mechanisms have long been confined to direct adenosine receptor antagonism, failing to explain the persistent neurodevelopmental consequences. Here, using cross-species models (rat PCE, astrocyte-specific Abcg1 knockout mice, and glucocorticoid-treated zebrafish) and multi-scale analyses, we demonstrate that PCE activates the maternal-fetal glucocorticoid axis, leading to dysregulation of the GR-miR-130b/301b-PPARγsignaling cascade in hippocampal astrocytes. This disrupts expression of the cholesterol transporter— ATP binding cassette subfamily G member 1 (ABCG1), impairing astrocytic cholesterol efflux and depriving neurons of cholesterol-rich microenvironments essential for synaptic development. Abcg1 knockout mice recapitulate PCE-induced synaptic defects, while astrocyte-specific ABCG1 overexpression or miR-130b/301b inhibition rescues neuronal cholesterol supply and synaptic structure. Luciferase assays confirm that miR-130b/301b directly suppress Pparγ-mediated Abcg1 transcription. Our findings identify the GR-miR-130b/301b-PPARγ-ABCG1 axis as a core mechanism of PCE-induced neurotoxicity, establishing astrocytic cholesterol transport as a potential intervention target and providing a shared molecular framework for evaluating central nervous system risks of glucocorticoid-disruptive agents.